Abstract | BACKGROUND & AIMS: METHODS: C57BL/6 wild-type and FGF21-knockout (FGF21-KO) mice were placed on methionine- and choline-deficient (MCD), high-fat, or control diets for 8-16 weeks. Mice were weighed, and serum and liver tissues were collected and analyzed for histology, levels of malondialdehyde and liver enzymes, gene expression, and lipid content. RESULTS: The MCD diet increased hepatic levels of FGF21 messenger RNA more than 50-fold and serum levels 16-fold, compared with the control diet. FGF21-KO mice had more severe steatosis, fibrosis, inflammation, and peroxidative damage than wild-type C57BL/6 mice. FGF21-KO mice had reduced hepatic fatty acid activation and β-oxidation, resulting in increased levels of free fatty acid. FGF21-KO mice given continuous subcutaneous infusions of FGF21 for 4 weeks while on an MCD diet had reduced steatosis and peroxidative damage, compared with mice not receiving FGF21. The expression of genes that regulate inflammation and fibrosis were reduced in FGF21-KO mice given FGF21, similar to those of wild-type mice. CONCLUSIONS:
FGF21 regulates fatty acid activation and oxidation in livers of mice. In the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.
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Authors | Ffolliott M Fisher, Patricia C Chui, Imad A Nasser, Yury Popov, Jeremy C Cunniff, Thomas Lundasen, Alexei Kharitonenkov, Detlef Schuppan, Jeffrey S Flier, Eleftheria Maratos-Flier |
Journal | Gastroenterology
(Gastroenterology)
Vol. 147
Issue 5
Pg. 1073-83.e6
(Nov 2014)
ISSN: 1528-0012 [Electronic] United States |
PMID | 25083607
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Fatty Acids
- Inflammation Mediators
- RNA, Messenger
- Recombinant Proteins
- fibroblast growth factor 21
- Fibroblast Growth Factors
- Methionine
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Topics |
- Animals
- Choline Deficiency
(complications)
- Disease Models, Animal
- Disease Progression
- Fatty Acids
(metabolism)
- Fibroblast Growth Factors
(administration & dosage, blood, deficiency, genetics, metabolism)
- Hepatitis
(genetics, metabolism, prevention & control)
- Inflammation Mediators
(metabolism)
- Infusions, Subcutaneous
- Lipid Peroxidation
(drug effects)
- Liver
(metabolism, pathology)
- Liver Cirrhosis
(genetics, metabolism, prevention & control)
- Methionine
(deficiency)
- Mice, Inbred C57BL
- Mice, Knockout
- Non-alcoholic Fatty Liver Disease
(blood, genetics, pathology, prevention & control)
- Oxidation-Reduction
- RNA, Messenger
(metabolism)
- Recombinant Proteins
(administration & dosage)
- Severity of Illness Index
- Time Factors
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